SIRT1 Controls Acetaminophen Hepatotoxicity by Modulating Inflammation and Oxidative Stress

Antioxidants & Redox Signaling
P RadaÁngela M Valverde

Abstract

Sirtuin 1 (SIRT1) is a key player in liver physiology and a therapeutic target against hepatic inflammation. We evaluated the role of SIRT1 in the proinflammatory context and oxidative stress during acetaminophen (APAP)-mediated hepatotoxicity. SIRT1 protein levels decreased in human and mouse livers following APAP overdose. SIRT1-Tg mice maintained higher levels of SIRT1 on APAP injection than wild-type mice and were protected against hepatotoxicity by modulation of antioxidant systems and restrained inflammatory responses, with decreased oxidative stress, proinflammatory cytokine messenger RNA levels, nuclear factor kappa B (NFκB) signaling, and cell death. Mouse hepatocytes stimulated with conditioned medium of APAP-treated macrophages (APAP-CM) showed decreased SIRT1 levels; an effect mimicked by interleukin (IL)1β, an activator of NFκB. This negative modulation was abolished by neutralizing IL1β in APAP-CM or silencing p65-NFκB in hepatocytes. APAP-CM of macrophages from SIRT1-Tg mice failed to downregulate SIRT1 protein levels in hepatocytes. In vivo administration of the NFκB inhibitor BAY 11-7082 preserved SIRT1 levels and protected from APAP-mediated hepatotoxicity. Our work evidenced the unique role of SIRT1 in APAP h...Continue Reading

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Citations

Sep 28, 2018·Antioxidants & Redox Signaling·Thomas Kietzmann
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Oct 12, 2021·Drug and Chemical Toxicology·Meltem ÖzgöçmenAli Mustafaoğlu

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Methods Mentioned

BETA
genetic modification
nuclear translocation
flow cytometry
PCR
immunoprecipitation
acetylation
ubiquitination
biopsies
surgical resection
biopsy

Software Mentioned

GraphPad
Cytomics FC500
GraphPad Prism

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